Relevance to Alzheimer?s Disease: Alzheimer?s Disease (AD) is a fatal, progressive neurodegenerative disease primarily affecting the elderly. Because of the aging population, AD is the sixth leading cause of death in the United States and is the only disease among the top ten causes of death that has no cure. AD is also the most common cause of dementia in the United States. AD is characterized by brain atrophy, amyloid plaques (composed of extracellular deposits of aggregated A? peptide), neurofibrillary tangles (composed predominantly of tau protein), neuron and synapse loss and dystrophic neurites. In addition to neuronal loss, evidence from both clinical and experimental studies strongly supports a key role for inflammation in the development of AD and the cognitive dysfunction of AD, and the role of microglial activation and macrophage activation in the progression of AD is being increasingly appreciated. Conditional depletion of plasminogen in peripheral blood is highly protective from A? deposition and the neuroinflammatory response and is accompanied by decreased microglial/macrophage activation and decreased numbers of perivascular macrophages present in the CNS in the 5XFAD Alzheimer?s Disease mouse model. A major gap in knowledge is the identity of the microglial/macrophage receptor mediating effects of plasminogen deletion on the innate neuroimmune response in AD. We discovered a novel, transmembrane plasminogen receptor, Plg-RKT. Plasminogen-dependent cell migration to inflammatory sites is regulated by Plg-RKT. In addition, plasminogen-dependent cytokine release from macrophages is promoted by Plg-RKT. Microglia express Plg-RKT and perivascular macrophages from wild type mice show high expression of Plg-RKT. Our long-term goal is to understand mechanisms by which Plg-RKT regulates physiologic and pathologic processes. Our objectives in this supplementary application are to determine the effects of Plg-RKT deletion on cognitive function in a murine model of AD and to determine the effects of Plg-RKT deletion on microglial and macrophage proinflammatory function in a murine model of AD. The central hypothesis to be addressed is that that Plg-RKT promotes neuroinflammation and neuronal loss in AD and consequent cognitive dysfunction by promoting microglial/macrophage activation and also by increasing the presence of perivascular macrophages in the CNS by promoting cell migration. To address our hypothesis, our specific aims are: 1) To test the hypothesis that Plg-RKT promotes cognitive dysfunction in AD mice and 2) To test the hypothesis that Plg-RKT promotes microglial and macrophage pro-inflammatory effects in AD mice. Innovation lies in the investigation of a new paradigm in which Plg-RKT is a crucial focal point for regulation of neuroinflammation in AD and the recognition of this new paradigm should bring about a major shift in current thinking regarding mechanisms by which neuroinflammation is regulated. The studies proposed are significant because they will advance understanding of how neuroinflammation is regulated in AD and may suggest Plg- RKT as a novel therapeutic target in AD.